Solomonamide analogue compounds, pharmaceuticals containing solomonamide analogue compounds, and processes for the preparation thereof

Abstract

Solomanamide analogs of Formula-I having anti-inflammatory activity, and viable synthetic routes for the preparation of such analogs, including the synthesis of macrocyclic core of Salomanamide analogs. The Solomanamide analogs of Formula-I or their pharmaceutical salt may be provided in a pharmaceutical composition and administered in an effective amount for the treatment of inflammation and/or pain.

Claims

1. A compound comprising: a solomonamide analogue of Formula I ##STR00022## wherein the Ring A is selected from the group consisting of a substituted or an unsubstituted aryl, a substituted or an unsubstituted heteroaryl, a substituted or an unsubstituted cycloalkyl, a substituted or an unsubstituted bicyclic compound, or a substituted or an unsubstituted heterocyclic compound; wherein the dipeptide is selected from the group consisting of two natural amino acids or two unnatural amino acids; wherein X is selected from the group consisting of O, NR.sup.a, S, S(O), S(O).sub.2, C(O), C(O)O, C(O)NR.sup.a, CR.sup.aR.sup.b; wherein the bond between X and an adjacent carbon atom is optionally a double bond; and wherein the bond between X and the adjacent carbon atom is optionally part of a 3 to 6-membered cycle having 1 or 2 hetero atoms; wherein R.sup.1 and R.sup.2 is independently selected from the group consisting of H, OH, OR, NR.sup.a, alkyl, aralkyl, substituted heteroatoms, unsubstituted heteroatoms, and amino acids; and wherein R.sup.1 and R.sup.2 substituents are attached to carbon atom optionally expresses chirality; wherein n is 0, 1, 2, or 3; wherein the R substituent is selected from the group consisting of alkyl, aralkyl, C(O)OR.sup.a, or C(O)NR.sup.aR.sup.a; R.sup.a is selected from the group consisting of H, OH, alkyl, and aralkyl; and R.sup.b is selected from the group consisting of H, OH, alkyl, aralkyl, OR, and NR.sup.aR.sup.a with a proviso that when the dipeptide is Gly-D-Ala, Ring A is the substituted aryl, X is C(O) and n is 1, then the solomonamide analogues chosen from ##STR00023##

2. The compound of claim 1, wherein said compound is selected from the group consisting of (R)-16-methoxy-3-methyl-3,4,6,7,9,10,11,12-octahydro-1H-benzo[h][1,4,7]triazacyclo-pentadecine-2,5,8,13-tetraone (1a); ##STR00024## (R,E)-3-methyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1b); ##STR00025## (R)-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1c); ##STR00026## (3R,9S,E)-3,9-dimethyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclo-pentadecine-2,5,8(9H)-trione (1d); ##STR00027## (3R,9S)-3,9-dimethyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclo-pentadecine-2,5,8(9H)-trione (1e); ##STR00028## (R,E)-16-methoxy-3-methyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1 f); ##STR00029## (R)-16-methoxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1g); ##STR00030## (3R)-12,13-dihydroxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]-triazacyclopentadecine-2,5,8(9H)-trione (1h); ##STR00031## (3R)-12,13-dihydroxy-16-methoxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1i). ##STR00032##

3. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt of the compound along with pharmaceutically acceptable excipients and/or vehicles, for treatment of inflammation and pain caused due to Cox I and Cox II enzymes, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, formamidinesulfonic acid, naphthalenedisulfonic acid, formic acid, fumaric acid, acetic acid, propionic acid, lactic acid, malic acid, citric acid, maleic acid, benzoic acid, malonic acid, tartaric acid, oxalic acid, succinic acid, a salt of sodium, a salt of potassium, a salt of calcium, a salt of magnesium and a salt of ammonium.

4. The pharmaceutical composition of claim 3, wherein said composition may be formulated into a dosage form chosen from tablets, pills, powders, capsules, injections, granules, suspension, syrup, liquid, microemulsion, topical creams, ointments, suppositories, sachets, troches and lozenges.

Description

DETAILED DESCRIPTION OF THE PRESENT INVENTION

(1) The present invention provides a process for the preparation of solomonamides analogues of Formula-I or their pharmaceutical salt as shown below to assess and identify safe and potential anti-inflammatory agents among the solomonamide chemotype:

(2) ##STR00021##

(3) wherein the Ring A substituent may be present or absent, and when present the Ring A substituent is selected from the group consisting of a substituted or an unsubstituted aryl, a substituted or an unsubstituted heteroaryl, a substituted or an unsubstituted cycloalkyl, a substituted or an unsubstituted bicyclic, or a substituted or an unsubstituted heterocyclic compound;

(4) wherein the dipeptide substituent is selected from the group consisting of two natural or unnatural amino acids which may include beta amino acids;

(5) wherein the X substituent is selected from the group consisting of O, NR.sup.a, S, S(O), S(O).sub.2, C(O), C(O)O, C(O)NR.sup.a, CR.sup.aR.sup.b; the bond between the X substituent and an adjacent carbon atom optionally represents double bond; the bond between the X; substituent and an adjacent carbon atom is optionally part of a 3 to 6-membered cycle which may contain 1 or 2 hetero atoms;

(6) wherein the R.sup.1 and R.sup.2 substituents are independently selected from the group consisting of H, OH, OR, NR.sup.a, alkyl, aralkyl, substituted or unsubstituted heteroatoms, where substituents are amino acids; and/or wherein the R.sup.1 and R.sup.2 substituents are attached to carbon atom optionally expresses chirality;

(7) wherein n is 0, 1, 2, or 3;

(8) wherein the R substituent is selected from the group consisting of alkyl, aralkyl, C(O)OR.sup.a, or C(O)NR.sup.aR.sup.a;

(9) R.sup.a is selected from the group consisting of H, OH, alkyl, aralkyl; and

(10) R.sup.b is selected from the group consisting of H, OH, alkyl, aralkyl, OR, NR.sup.aR.sup.a.

(11) Optionally, the dipeptide moiety in compound of Formula-I may be replaced with mono peptide or tripeptide.

(12) The present invention provides novel synthetic route for the preparation of solomonamide analogues to overcome the limitations involved in the availability of the natural cyclic peptide.

(13) The present invention provides one or more processes for synthesis of potent anti-inflammatory cyclic peptides, particularly macrocyclic core of solomonamide analogues of Formula 1a, the process comprising the steps of: i. palladium-catalyzed acylation of substituted acetanilides and methyl 6-oxohexanoate in the presence of TBHP and an organic solvent at a suitable temperature, to obtain carbonyl-acetanilides compound; ii. protecting carbonyl-acetanilides compound with dithiol in the presence of BF3.Et.sub.2O, to yield dithioketal compound; iii. protecting of dithioketal compound, followed by deprotecting in the presence of a cleavage reagent to afford a free amine compound; iv. coupling of the free amine compound with a protected amino acid/peptide, followed by hydrolyzing to furnish an acyclic precursor; v. subjecting the acyclic amino acid to macrolactamization using HATU, followed by deprotection, to obtain a macrocyclic core of solomonamide of formula 1a.

(14) According to the process, Pd catalyzed direct ortho-acylation of substituted acetanilide with methyl-6-oxohexanoate affording the o-acyl acetanilides, wherein Pd(OCOCF.sub.3).sub.2 gave the best result as a Pd catalyst for the coupling reaction in the presence of tert-butyl hydroperoxide (C. Li, L. Wang, P. Li, W. Zhou, in Chem. Eur. J. 2011, 17, 1020). The suitable temperature for acylation is maintained in between 90-120 C.

(15) The substituents of acetanilides are selected from the group consisting of H, (C1-C6)alkoxy, hydroxyl, preferably acetanilides derivatives are selected from group consisting of 3-methoxy acetanilide, 3-hydroxyl-acetanilide; preferably substituted acetanilides is 3-methoxy acetanilide.

(16) The installation of dithiol is performed in presence of (C1-C6)alkane dithiol, aryl dithiol or aralkyl dithiol at room temperature (20-35 C.).

(17) The protecting of dithioketal compound is carried out in a two step sequence, firstly deacetylation which is functionalized in presence of alcoholic acid, preferably methanolic HCl at a temperature range of 30-50 C., followed by N-acylation in the presence of protected amino acid derivatives including Fmoc, Boc and Cbz protecting groups, preferably Fmoc-D-Alanyl-Chloride.

(18) The hydrolysis of the dithioketal compound to obtain the corresponding acid is carried out in the presence of aqueous alkali metal hydroxide such as NaOH, KOH, LiOH, CsOH in a suitable solvent. Further, the HATU mediated macrolactamization is performed in the presence of mixed organic solvent system, such as THF/DMF, THF/CH.sub.2Cl.sub.2, and base such as triethylamine, diisopropylethylamine, ammonia and like thereof.

(19) The present invention provides a process for synthesis of a solomonamide analogue of formula Ia, as depicted in FIG. 1. The process comprises preparation of key intermediate 6, which is further converted to desired solomonamide analogue compound 1a. The process for the preparation of key intermediate 6 comprises reacting of compound 2 with compound 3 in the presence of Pd(TFA).sub.2 and TBHP at 110 C. to obtain compound 4, that further treated with 1,3 propane dithiol and BF.sub.3.Et.sub.2O at room temperature (20-35 C.) to obtain compound 5, which is subsequently hydrolyzed in the presence of methanolic HCl to obtain key intermediate 6 in high yield. Further compound 6 is treated to yield desired solomonamide compound 1a, which comprises reaction of compound 6 with Fmoc-D-Alanyl-Chloride 12 to obtain compound 13, which is further hydrolyzed in presence of piperdine in THF to give free amine compound 14, followed by treating with N-Boc glycine to give compound 15. The compound 15 is subsequently hydrolyzed in the presence of LiOH to afford compound 16. The deprotection Boc group of compound 16 is carried out in the presence of TFA in DCM followed by HATU mediated macrolactamization to obtain an intermediate, which is subsequently deprotected in the presence of HgO and BF.sub.3.Et.sub.2O to furnish solomonamide compound 1a.

(20) The present invention provides the preparation of compound 9, a key intermediate useful for the preparation of compound of formula 1a as depicted in FIG. 2. The process comprises, reacting m-Anisidine (2a) with 6-Methoxy-6-oxohexanoic acid (7) in the presence of HOBt in DCC at room temperature (20-35 C.) to obtain compound 8. The compound 8 thus obtained is further converted to desired key intermediate compound 9 by irradiating the same in the presence of acetonitrile or a suitable solvent.

(21) Alternately, the compound 9 is prepared by oxidative cleavage of compound 10 in methanol in the presence of NaIO.sub.4 in water at room temperature (20-35 C.) to obtain compound 11, further compound 11 in dioxane is hydrolyzed in acidic condition, followed by treatment with SOCl.sub.2 in the presence of MeOH at 0 C., and stirred for 16 h at room temperature (20-35 C.). After completion of starting material, the reaction mass is evaporated to dryness, and neutralized with sat.NaHCO.sub.3 sol, followed by extraction and purification to afford compound 9 in high yield (70% or above). The spectral data is found identical with above compound 9 (FIG. 3).

(22) Similarly, compound 9 may be converted to compound of formula 4 by simple acetylation of aniline group and proceed with the subsequent steps as described in FIG. 1, to obtain the macrocyclic core of solomonamide analogue compound 1a.

(23) The present invention provides a process for the synthesis of solomonamide analogues of Formula-1, encompasses the compounds of formula 1b, 1c, 1d, 1e, 1f, 1g, 1h and 1i respectively, in the presence of 2,2,2-trichloroethyl hex-5-enoate (FIG. 4) comprising the steps of: i. coupling of halo-aniline derivatives (2) with dipeptide in presence of coupling agent and organic solvent to obtain halo-dipeptide complex (17), optionally followed by Stille coupling to obtain vinyl dipeptide intermediate; ii. refluxing the dipeptide complex compound of step i) with 2,2,2-trichloroethyl hex-5-enoate (19) in presence of catalyst to obtain intermediate compound (20); iii. Further the intermediate compound (20) is converted to solomonamide analogue compounds of formula 1b, 1c, 1d, 1e, 1f, 1g 1h and 1i by employing the known methods.

(24) According to certain aspects of the process of the present invention, the halo aniline derivatives are selected from the group consisting of o-halo aniline, halogen substituted (C1-C6)alkoxy aniline, preferably 2-halo-m-anisidine, or 2-halo m-hydroxy aniline wherein the halo group is selected from the group consisting of Cl, I, F, Br etc.

(25) Dipeptide complex is selected from the group as mentioned herein above, preferably the dipeptide complex is Boc-Gly-D-Ala-OH; where coupling agents are not limited to HATU, HOBt, HOAt TATU, TBTU, PyBOP in base, where suitable base is disopropyl ethylamine, tertiary butyl amine, methylamine, triethylamine, ammonia like thereof.

(26) Further, the addition of 2,2,2-trichloroethyl hex-5-enoate is carried out in the presence of metal based catalyst, wherein the metal is selected from the group consisting of Ru, Pd, Pt, Rh, Ag, Au, Ni, preferably the catalyst is selected from [(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium] (also referred as Hoveyda Grubbs2nd generation catalyst) or Pd(II) acetate and TEA. The deprotection of Boc group is carried out in the presence of 10-30% TFA in DCM, followed by cyclization by means of 2-hydroxypyridine in toluene for 35-45 hrs.

(27) It is found that by employing the aniline derivatives as starting material the yield of desired solomonamide analogue is obtained in the range of 33%-95%.

(28) Optionally, the unsaturated solomonamide analogues of formula 1b, 1d and 1f are hydrogenated to saturated solomonamide analogue in the presence of H.sub.2 gas and Pd/C catalyst in suitable solvent to obtain compound of formula 1c, 1e and 1g, respectively. Additionally, the macrocyclic core of solomonamide of formula 1b is further converted to other analogues of formula 1h by dihydroxylation.

(29) The present invention provides a process for the synthesis of 2,2,2-trichloroethyl hex-5-enoate (19), which comprises reaction of 5-hexenoic acid (21) and trichloro ethanol in CH.sub.2Cl.sub.2, followed by addition of DCC, DMAP with stirring for 10-12 h at room temperature i.e. 20 to 35 C. The reaction mixture is then filtered and concentrated in vacuo, purification by column chromatography using pet, ether to afford compound 2,2,2-trichloroethyl hex-5-enoate (19) in high yield i.e. more than 60% (FIG. 5).

(30) A process for synthesis of key fragment 31 [4-Amino-6-(20-amino-40-hydroxyphenyl)-3-hydroxy-2-methyl-6-oxo hexanoic acid (AHMOA)], of solomonamide analogue of Formula-I comprising the steps of: a) subjecting aldehyde compound 24 to crotylation reaction in the presence of freshly activated CrCl.sub.2 to give diastereomers 25a and 25b; b) converting 25b to corresponding cyclic carbamates 26b in the presence of NaH at temperature range of 50-70 C. followed by TBS deprotecting and Jones oxidation to afford carboxylic acid 27; c) coupling TIPS protected m-amino-phenol 28 with compound 27 in the presence of DCC, HOBt to provide amide compound 29; d) photolysing of amide 29 using Hg lamp (254 nm) under dilute conditions in acetonitrile to furnish the photo-Fries rearranged product 30; e) oxidative cleavage of olefin in 30 followed by further oxidation furnished carboxylic acid i.e. key fragment 31 in good yield.

(31) According to the process, the aldehyde (24) is subjected to a key crotylation reaction to introduce the new chiral centers present in the target molecule. Freshly activated CrCl.sub.2 gives a 1:2 ratio of diastereomers (25a) and (25b) in which the desired (25b) is the major compound. The stereochemistry of more deshielded chiral protons is established by comparing their proton coupling constants in the corresponding cyclic carbamates (26a) and (26b), as depicted in FIG. 6.

(32) Further, the undesired isomer 25a can be converted to 25b via an inversion reaction that makes the process cost effective. The complete stereostructure of 26b as drawn is further confirmed by the single X-ray crystal structure. The carboxylic acid 27 prepared from cyclic carbamate 26b (TBS deprotection followed by Jones oxidation) is coupled with TIPS protected m-amino-phenol 28 to provide compound 29. Attempts to form sp.sup.2-sp.sup.2-CC bond formation through CH activation in a similar way to that of the model substrate resulted in very poor yields of the desired product. Therefore, the photolysis of the amide 29 using Hg lamp (254 nm) under dilute conditions in acetonitrile furnished the photo-Fries rearranged product 30 in a highly regioselective manner. Further, oxidative cleavage of olefin in 30 followed by further oxidation furnished carboxylic acid i.e. key fragment 31 in good yield. Thus, the key fragment AHMOA is prepared in a protected form, which will be carried forward to the total synthesis of natural solomonamides.

(33) The organic solvent used in the instant process is not limited to polar solvents such as, DCM, THF, Ethyl acetate, Acetone, DMF, Acetonitrile, DMSO, isopropanol, n-propanol, ethanol, methanol, n-butanol, tert-butanol or mixtures thereof or aqueous combination thereof, and non polar organic solvent such as chloroform, toluene, diethyl ether, cyclohexane, hexane, 1,4 dioxane or mixtures thereof.

(34) It will also be appreciated that, when two or more asymmetric centers are present in the compounds of the present invention, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the present invention. The present invention encompasses all stereoisomers and enantiomers of compounds of formula I. The present invention further encompasses pharmaceutical salts of the compound of formula I, such as acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, formamidinesulfonic acid, naphthalenedisulfonic acid, formic acid, fumaric acid, acetic acid, propionic acid, lactic acid, malic acid, citric acid, maleic acid, benzoic acid, malonic acid, tartaric acid, oxalic acid and succinic acid.

(35) Pharmaceutically acceptable salts further include salts of customary bases, such as for example alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines. All the intermediates and the final solomonamide analogues involved in the above preparation were characterized by NMR and Mass spectrometry.

(36) Although the route of the synthesis for the preparation of solomonamide analogue(s) depicted by the present invention involves multi steps, however, the yields and the purity of each intermediate and the final compound involved in the instant route makes this as feasible choice for preparation of the novel solomonamide analogues.

EXAMPLES

(37) The following examples are given by way of illustration; and therefore, the following examples should not be construed to limit the scope of the present invention.

Example 1

Methyl 6-(2-acetamido-4-methoxyphenyl)-6-oxohexanoate (4)

(38) N-(3-methoxyphenyl)acetamide 2 (1 g, 6 mmol) and Pd(TFA).sub.2 (100 mg, 0.3 mmol) were loaded in sealed tube with a stirbar. Toluene (12 mL) was added into the tube. The mixture was then stirred for about 1-2 min. Methyl 6-oxohexanoate 3 (1.74 g, 12 mmol), TBHP (6 M in decane, 2 mL) were loaded into the tube. The tube was stirred at 90 C. for 24 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel 100-200 mesh, 1:9 Ethyl acetate:Pet ether) to afford 4 (1.1 g, 65%) as a pale yellow solid.

(39) IR .sub.max(film): cm.sup.1 3446, 2925, 2853, 1738, 1733, 1698, 1645, 1615, 1581, 1526, 1435, 1367, 1246, 866; .sup.1H NMR (200 MHz, CDCl.sub.3): 12.12 (bs, 1H), 8.42 (d, 1H, J=2.7 Hz), 7.82 (d, 1H, J=9.0 Hz), 7.03 (dd, 1H, J=2.7, 9.0 Hz), 3.87 (s, 3H), 3.67 (s, 3H), 2.97 (m, 2H), 2.38 (m, 2H), 2.23 (s, 3H), 1.73 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): 202.7, 173.8, 169.9, 164.7, 143.9, 132.7, 114.7, 109.6, 104.0, 55.6, 51.6, 39.2, 33.9, 25.7, 24.5, 24.1; MS: 330 (M+Na).sup.+

Example 2

Methyl 5-(2-(2-acetamido-4-methoxyphenyl)-1,3-dithian-2-yl)pentanoate (5)

(40) To a solution of 4 (1 g, 3.4 mmol) in DCM (20 mL) was added 1,3 propane dithiol (0.85 mL, 8.5 mmol) and BF.sub.3.Et.sub.2O (1 mL, 8.5 mmol) and stirred at 25 C. for 13 h. The reaction mixture was diluted with DCM (40 mL), added sat. NaHCO.sub.3 and the organic layer was dried and concentrated under reduced pressure. The crude was subjected to purification by column chromatography (silica gel 100-200, 15:85 Ethyl acetate:Pet ether) to afford 5 (1.2 g, 89%) as a colorless liquid

(41) IR .sub.max(film): cm.sup.1 2949, 1736, 1694, 1525, 1464, 1424; .sup.1H NMR (400 MHz, CDCl.sub.3): 9.81 (bs, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.68 (bs, 1H), 6.66 (dd, J=2.7, 8.9 Hz, 1H), 3.79 (s, 3H), 3.60 (s, 3H), 2.83-2.73 (m, 4H), 2.20-2.17 (m, 2H), 2.15 (s, 3H), 2.11-2.07 (m, 2H), 2.00-1.95 (m, 2H); 1.53-1.46 (m, 2H), 1.30-1.17 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): 173.8, 167.8, 159.5, 137.7, 133.2, 119.8, 110.1, 110.0, 57.4, 55.3, 51.5, 40.5, 33.6, 28.1 (2C), 25.1, 24.9, 24.8, 23.7; MS: 420 (M+Na).sup.+;

Example 3

Methyl 5-(2-(2-amino-4-methoxyphenyl)-1,3-dithian-2-yl)pentanoate (6)

(42) To a stirred solution of 5 (200 mg, 0.5 mmol) in Methanol (5 mL) was added 4N HCl (3 mL) and then heated at 40-50 C. for 4 h. Methanol was removed under reduced pressure, the residue was basified with sat. NaHCO.sub.3 (pH=10) and extracted with Ethyl acetate (15 mL2). The combined organics were dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by column chromatography (silica gel 100-200, 10:90 Ethyl acetate:Pet ether) to afford 6 (145 mg, 81%) as a colorless liquid.

(43) IR .sub.max(film): cm.sup.1 3424, 3316, 2949, 2836, 1731, 1617, 1571, 1501, 1437, 1211, 910, 732; .sup.1H NMR (200 MHz, CDCl.sub.3): 7.70 (d, 1H, J=8.7 Hz), 6.33 (dd, 1H, J=8.7, 2.6 Hz), 6.18 (d, 1H, J=2.6 Hz), 4.88 (bs, 2H), 3.77 (s, 3H), 3.62 (s, 3H), 2.66-2.87 (m, 4H), 2.18-2.27 (m, 4H), 1.94-2.00 (m, 2H), 1.47-1.62 (m, 2H), 1.18-1.34 (m, 2H): MS 378 (M+Na).sup.+

Example 4

(R)-methyl-5-(2-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-Methoxyphenyl)-1,3-dithian-2-yl)pentanoate (13)

(44) To a solution of 6 (145 mg, 0.4 mmol) and D-Fmoc-Ala-Cl 12 (148 mg, 0.4 mmol) in dry DCM (5 mL), saturated aq. NaHCO.sub.3 (2.5 mL) was added and stirred for 6 h at 25 C. The reaction mixture was diluted with DCM (10 mL) and the organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200, 3:7 ethyl acetate-pet ether) to afford 13 (175 mg, 66%) as a colorless viscous liquid.

(45) [].sub.D.sup.27=25.0 (c=0.3, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3273, 1732, 1682, 1610, 1575; .sup.1H NMR (200 MHz, CD.sub.3OD): 7.87-7.69 (m, 5H), 7.42-7.29 (m, 5H), 6.75 (dd, J=2.9, 8.9 Hz, 1H), 4.48-4.15 (m, 4H), 3.77 (s, 3H), 3.52 (s, 3H), 2.72-2.54 (m, 4H), 2.21-1.88 (m, 6H), 1.43 (d, J=7.0 Hz, 3H), 1.38-1.28 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): 173.9, 170.2, 159.5, 155.8, 143.8 (2C), 141.3 (2C), 137.1, 133.3, 127.7 (2C), 127.1 (2C), 125.1(2C), 120.5, 120.0 (2C), 110.6, 109.8, 67.1, 57.4, 55.4 (2C), 51.9, 51.5, 47.2, 40.4, 33.6, 28.0, 24.7 (2C), 23.7, 19.0; MS: 671 (M+Na).sup.+;

Example 5

(R)-Methyl-5-(2-(2-(2-aminopropanamido)-4-methoxyphenyl)-1,3-dithian-2-yl)pentanoate (14)

(46) To a solution of 13 (250 mg, 0.4 mmol) in THF (5 mL), piperidine (0.2 mL) was added and stirred at 23 C. e for 2 h. Reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200, 1:24 methanol-DCM) to afford 13 (140 mg, 85%) as a colorless viscous liquid.

(47) [].sub.D.sup.25=5.8 (c=0.6, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3245, 2950, 1735, 1679, 1608, 1043; .sup.1H NMR (400 MHz, CD.sub.3OD): 7.84 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 6.76 (dd, J=2.7 Hz, 9.0 Hz, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 3.58-3.53 (m, 1H), 2.84-2.79 (m, 4H), 2.23-2.17 (m, 4H), 2.02-1.90 (m, 2H), 1.53-1.45 (m, 2H), 1.39 (d, J=7.0 Hz, 3H), 1.27-1.19 (m, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 176.5, 175.5, 160.7, 137.9, 134.1, 124.2, 113.1, 110.9, 57.3, 55.8, 52.6, 51.9, 40.8, 34.4, 28.9, 25.9, 25.8 (2C), 25.1, 21.3; MS: 449 (M+Na).sup.+.

Example 6

(R)-Methyl-5-(2-(2-(2-(2-((tert-butoxycarbonyl)amino)acetamido)propanamido)-4-methoxy phenyl)-1,3-dithian-2-yl)pentanoate (15)

(48) To a solution of 14 (120 mg, 0.3 mmol) and Boc-Gly-OH (55 mg, 0.3 mmol) in dry DCM (5 mL) EDC.HCl (48 mg, 0.3 mmol), HOBt (42 mg, 0.3 mmol), Et.sub.3N (0.1 mL, 0.6 mmol) were added and stirred for 14 h at 23 C. The reaction mixture was diluted with DCM (10 mL), washed with 1N HCl (10 mL), saturated aq. NaHCO.sub.3 solution (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200, 1:30 methanol-DCM) to afford 15 (120 mg, 75%) as a colorless viscous liquid.

(49) [].sub.D.sup.24=18.3 (c=1.0, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3294, 2937, 1718, 1676, 1609, 1169, 1045; .sup.1H NMR (400 MHz, CD.sub.3OD): 7.90 (d, J=8.9 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.80 (dd, J=2.3, 8.8 Hz, 1H), 4.45 (q, J=7.0 Hz, 1H), 3.84 (s, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 2.81-2.73 (m, 4H), 2.23-2.19 (m, 2H), 2.11-1.91 (m, 4H), 1.50-1.45 (m, 14H), 1.21-1.14 (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD): 175.7, 172.8, 172.6, 160.8, 158.2, 137.6, 134.7, 123.9, 113.1, 111.3, 80.7, 57.9, 55.8, 52.0, 51.7, 44.7, 41.2, 34.3, 29.0 (2C), 28.7 (3C), 26.0, 25.7, 24.8, 17.7; MS: 606 (M+Na).sup.+.

Example 7

(R)-5-(2-(2-(2-(2-((tert-butoxycarbonyl)amino)acetamido)propanamido)-4-methoxy phenyl)-1,3-dithian-2-yl)pentanoic acid (16)

(50) To a solution of 15 (120 mg, 0.2 mmol) in THF:MeOH (3:2, 5 mL), LiOH (26 mg, 0.6 mmol, in 1 mL water) was added and stirred for 3 h at 25 C. Solvent was removed under reduced pressure and the residue was acidified with 1 N HCl (pH3) and extracted with ethyl acetate (10 mL2). The combined organics were dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to afford 16 (110 mg, 94%) as colorless liquid.

(51) [].sub.D.sup.25=5.0 (c=0.5, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3307, 2933, 1714, 1669, 1610, 1245, 1045; .sup.1H NMR (400 MHz, CD.sub.3OD): 7.88 (d, J=8.8 Hz, 1H), 7.40 (bs, 1H), 6.77 (dd, J=2.5, 8.8 Hz, 1H), 4.46 (q, J=7.3 Hz, 1H), 3.83 (s, 2H), 3.79 (s, 3H), 2.87-2.72 (m, 4H), 2.19-2.07 (m, 4H), 2.09-1.93 (m, 2H), 1.48-1.43 (m, 14H), 1.22-1.20 (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD): 177.7, 175.6, 173.2, 173.0, 161.1, 138.0, 135.1, 124.3, 113.5, 111.7, 81.0, 58.3, 56.2, 52.1, 45.1, 41.7, 35.0, 31.2, 29.4 (3C), 26.4, 26.3, 25.3, 21.2, 18.2; MS: 592 (M+Na).sup.+.

Example 8

(R)-16-Methoxy-3-methyl-3,4,6,7,9,10,11,12-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8,13-tetraone (1a)

(52) To a solution of 16 (40 mg, 0.07 mmol) in DCM (3 mL), TFA (0.9 mL) was added and stirred at 23 C. for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was taken up in dry DCM (14 mL), HATU (80 mg, 0.21 mmol) and Et.sub.3N (0.05 mL, 0.35 mmol) were added and the resulting reaction solution was stirred at room temperature for 16 h. Reaction mixture was diluted with DCM (10 mL) and washed with 1N HCl (5 mL) and saturated aq. NaHCO.sub.3 solution (5 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure. The residue (20 mg, 0.04 mmol) obtained after the evaporation of the solvent was dissolved in THF-water (85:15, 3 mL), HgO (22 mg, 0.1 mmol) and BF.sub.3.Et.sub.2O (0.01 mL, 0.1 mmol) were added and stirred at room temperature for 4 h. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (5 mL), washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400, 1:19 methanol:DCM) to afford 1a as a white solid (8 mg, 32% over 3 steps).

(53) Mp=158-160 C.; [].sub.D.sup.24=29.0 (c=0.2, CHCl.sub.3); IR .sub.max(film): cm.sup.1 2924, 2854, 1632, 1540, 1040; .sup.1H NMR (400 MHz, CD.sub.3OD): 8.21 (d, J=2.8 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 6.71 (dd, J=9.2, 2.8 Hz, 1H), 4.54 (d, J=15.1 Hz, 1H), 4.30 (q, J=7.4 Hz, 1H), 3.85 (s, 3H), 3.68 (d, J=15.1 Hz, 1H), 3.01-2.98 (m, 2H), 2.11-1.96 (m, 2H), 1.79-1.58 (m, 4H), 1.49 (d, J=7.4 Hz, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD): 203.3, 175.8, 173.5, 171.3, 165.3, 142.8, 133.6, 117.0, 109.6, 105.4, 55.5, 52.1, 43.4, 38.3, 36.1, 26.9, 21.4, 16.6; MS: 384 (M+Na).sup.+.

Example 9

Methyl 6-((3-methoxyphenyl)amino)-6-oxohexanoate (8)

(54) To a solution of 2a (2 g, 16.26 mmol) and 6-Methoxy-6-oxohexanoic acid 7 (2.8 g, 17.88 mmol) in DCM (30 ml) HOBt (2.4 g, 17.88 mmol) was added at 0 C. followed by DCC (3.6 g, 17.88 mmol). This reaction mass was stirred at 22 C. for 16 h. Reaction mass was filtered through celite, filtrate was evaporate to dryness, purified by column chromatography (silica gel 230-400, 4:96 Methanol:DCM) to afford 8 as white Solid (3 g, 70%).

(55) .sup.1H NMR (200 MHz, CDCl.sub.3): 7.62 (bs, 1H), 7.34 (bs, 1H), 7.27-7.16 (m, 1H), 7.01-6.97 (d, 1H, J=8.08 Hz), 6.68-6.63 (dd, 1H, J=1.79, 8.37 Hz), 3.79 (s, 3H), 3.68 (s, 3H), 2.40-2.34 (m, 4H), 1.83-1.66 (m, 4H); MS: 288 (M+Na).sup.+.

Example 10

Methyl 6-(2-amino-4-methoxyphenyl)-6-oxohexanoate (9)

(56) Compound 8 (100 mg) was dissolved in acetonitrile (35 ml), solution was purged with Argon for 10 min. This solution was irradiated with Hg lamp (200-400 nm) for 10 h. After removal of the solvent under reduced pressure, the residues were purified by column chromatography (silica gel 100-200, 4:96 Ethyl acetate:Pet ether) to afford 9 as yellow semi-solid (30 mg, 30%).

(57) .sup.1H NMR (200 MHz, CDCl.sub.3): 7.68 (d, 1H, J=8.96 Hz), 6.42 (bs, 1H), 6.42-6.6.20 (dd, 1H, J=2.39 Hz, 9.06 Hz), 6.07-6.06 (d, 1H, J=2.39 Hz), 3.80 (s, 3H), 3.67 (s, 3H), 2.92-2.86 (m, 2H), 2.41-2.34 (m, 2H), 1.76-1.69 (m, 4H); MS: 288 (M+Na).sup.+.

Example 11

10-methoxy-3,4,5,6-tetrahydro-1H-benzo[b]azonine-2,7-dione (11)

(58) To a solution of 10 (3 g, 14.92 mmol) in MeOH:H.sub.2O (1:1, 40 ml), NaIO.sub.4(3.8 g, 17.92 mmol) in H.sub.2O (10 ml), was added at 0 C., stirred at 23 C. for 16h. Solid thus formed was filtered, filtrate was evaporated to dryness, dissolved in EtOAc (200 ml), washed with H.sub.2O (25 ml), Brine (15 ml), dried over Na.sub.2SO.sub.4, evaporated to dryness, purified by column chromatography (silica gel 230-400, 5:95 Methanol:DCM) to afford compound 11 as a light brown solid (1.9 g, 55%).

Example 12

Methyl 6-(2-amino-4-methoxyphenyl)-6-oxohexanoate (9)

(59) To a solution of 11 (1.9 g, 8.15 mmol) in dioxane (15 ml), 6N HCl (8 ml) was added, refluxed for 6h. Reaction was monitored by TLC and after completion of Starting material, reaction mass was evaporated to dryness, to give black solid. It was dissolved in MeOH (40 ml) and SOCl.sub.2 (0.72 ml, 9.6 mmol) was added drop wise at 0 C., stirred for 16h at RT. After completion of starting material, reaction mass was evaporated to dryness, neutralized with sat.NaHCO3 sol, extracted with EtOAc (325 ml), combined organic layer was washed with H.sub.2O (15 ml), Brine (10 ml), dried over Na.sub.2SO.sub.4, evaporated to dryness, purified column chromatography (silica gel 100-200, 5:95 Ethyl acetate:Pet ether) to afford compound 9 as a light yellow semi solid (1.47 g, 70%). Spectral data was compared with above compound 9 and found that they are identical.

Example 13

Synthesis of tert-butyl(R)-(2-((1-((2-bromophenyl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl) carbamate (17a)

(60) To a mixture of 2-bromoaniline 2b (1.0 g, 5.8 mmol), Boc-Gly-D-Ala-OH (1.4 g, 5.8 mmol) in 20 mL CH.sub.2Cl.sub.2. HATU (3.3 g, 8.7 mmol), Diisopropyl ethylamine (3.0 mL) were added and stirred at 24 C. for 14 h, the reaction mixture was diluted with CH.sub.2Cl.sub.2 (30 mL) and washed with 1N HCl (15 mL) and sat. NaHCO.sub.3 solution (15 mL) organic layer was separated, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure. Purification by column chromatography with EtOAc/CH.sub.2Cl.sub.2 (2:3) yielded compound 17a (1.2 g, 52%) as a pale yellow sticky liquid.

(61) .sup.1H NMR (500 MHz, CD.sub.3OD): 7.71 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 4.58 (q, J=7.3 Hz, 1H), 3.78 (s, 2H), 1.49 (d, J=7.3 Hz, 3H), 1.43 (s, 9H); .sup.13C NMR (125 MHz, CD.sub.3OD): 170.6, 169.7, 155.6, 133.9, 130.9, 126.2, 125.5, 124.5, 116.1, 77.9, 52.9, 48.0, 25.7 (3C), 14.9; MS: 422 (M+Na).sup.+.

Example 14

Synthesis of tert-butyl(R)-(2-oxo-2-((1-oxo-1-((2-vinylphenyl)amino)propan-2-yl)amino)ethyl)carbamate (18)

(62) To a solution of compound 17a (0.5 g, 1.2 mmol) in toluene (10 mL) under argon, vinyl tributyl tin (0.4 mL, 1.3 mmol) followed by Pd.sub.2(dba).sub.3 (60 mg, 0.06 mmol), triphenyl phosphine (65 mg, 0.25 mmol) were added and refluxed for 10h. Further reaction mixture was concentrated in vacuo. Purification by column chromatography with EtOAc/CH.sub.2Cl.sub.2 (1:3) yielded compound 18 (332 mg, 76%) as a pale yellow solid.

(63) .sup.1H NMR (400 MHz, CD.sub.3OD): 7.62-7.59 (m, 1H), 7.32-7.22 (m, 3H), 6.88 (dd, J=17.8, 11.3 Hz, 1H), 5.75 (d, J=17.8 Hz, 1H), 5.31 (d, J=11.3 Hz, 1H), 4.55 (q, J=7.3 Hz, 1H), 3.75 (s, 2H), 1.48 (d, J=7.3 Hz, 3H), 1.41 (s, 9H); .sup.13C NMR (100 MHz, CD.sub.3OD): 171.2, 169.6, 155.7, 132.3, 132.0, 130.6, 126.8, 126.3, 125.0, 124.9, 123.9, 113.4, 77.9, 47.8, 41.8, 25.7 (3C), 15.1; MS: 370 (M+Na).sup.+.

Example 15

Synthesis of 2,2,2-trichloroethyl hex-5-enoate (19)

(64) To a stirred solution of 5-hexenoic acid 21 (1.0 g, 8.7 mmol) and trichloro ethanol (0.84 ml, 8.7 mmol) in 20 mL CH.sub.2Cl.sub.2, DCC (1.8 g, 8.7 mmol), DMAP (1.0 g, 8.7 mmol) were added and stirred for 10 h at 23 C. reaction mixture was filtered and concentrated in vacuo, purification by column chromatography using pet, ether to afford compound 19 (1.4 g, 61%) as a colorless liquid.

(65) .sup.1H NMR (400 MHz, CDCl.sub.3): 5.83-5.73 (m, 1H), 5.07-5.09 (m, 2H), 4.74 (s, 2H), 2.47 (t, J=7.45 Hz, 2H); 2.13 (q, J=6.99 Hz, 2H), 1.80 (quin, J=6.8, 14.7 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): 171.9, 137.3, 115.7, 95.0, 73.8, 33.1, 32.9, 23.8; MS: 267 (M+Na).sup.+;

Example 16

Synthesis of 2,2,2-trichloroethyl(S)-2-methylhex-5-enoate (19)

(66) Synthesized from (S)-2-methylhex-5-enoic acid by following procedure for the synthesis of 19 in 70% yield as colorless liquid

(67) .sup.1H NMR (200 MHz, CDCl.sub.3): 5.87-5.67 (m, 1H), 5.07-4.94 (m, 2H), 4.73 (s, 2H), 2.70-2.52 (m, 1H); 2.16-2.05 (m, 2H), 1.94-1.76 (m, 1H), 1.64-1.46 (m, 1H), 1.22 (d, J=7.0, 3H); .sup.13C NMR (50 MHz, CDCl.sub.3): 174.8, 137.5, 115.4, 95.1, 73.8, 38.7, 32.5, 31.2, 16.8; MS: 281 (M+Na).sup.+;

Example 17

Synthesis of 2,2,2-trichloroethyl(R,E)-6-(2-(2-(2-((tert-butoxycarbonyl)amino)acetamido)propanamido)phenyl)hex-5-enoate (20a)

(68) To a stirred solution of compound 18 (0.4 g, 1.1 mmol) and compound 19 (365 mg, 1.5 mmol) in CH.sub.2Cl.sub.2, Hoveyda Grubbs2.sup.nd generation catalyst (36 mg, 5 mol %) was added and refluxed for 18h, then the reaction mixture was cooled to rt concentrated in vacuo. purification by column chromatography with EtOAc/CH.sub.2Cl.sub.2 (2:3) yielded compound 20a (295 mg, 45%) as colorless liquid.

(69) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24 (bs, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.9 (bs, 1H), 6.49 (d, J=15.4 Hz, 1H), 6.11-6.03 (m, 1H), 5.30 (bs, 1H), 4.73 (s, 2H), 4.70-4.66 (m, 1H), 3.85-3.82 (m, 2H), 2.55 (t, J=7.3 Hz, 2H), 2.34 (q, J=6.6 Hz, 1H), 1.91 (quin, J=7.3, 14.5 Hz), 1.48 (d, J=7.3 Hz, 3H), 1.42 (s, 9H); .sup.13C NMR (100 MHz, CDCl.sub.3): 172.3, 170.3, 169.9, 156.1, 133.8, 133.1, 130.6, 127.8, 126.8, 126.2, 125.5, 123.7, 94.9, 80.6, 73.9, 49.4, 44.5, 33.3, 32.5, 28.3 (3C), 24.0, 17.6; MS: 586 (M+Na).sup.+.

Example 18

Synthesis of 2,2,2-trichloroethyl(S,E)-6-(2-((R)-2-(2-((tert-butoxycarbonyl)amino)acetamido)propanamido)phenyl)-2-methylhex-5-enoate (20b)

(70) Synthesized from 19 and 18 by following procedure for the synthesis of 20a in 35% yield as colorless liquid.

(71) .sup.1H NMR (200 MHz, CDCl.sub.3): 8.22 (bs, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.20-7.10 (m, 2H), 6.92 (bs, 1H), 6.47 (d, J=15.6 Hz, 1H), 6.12-6.98 (m, 1H), 5.29 (bs, 1H), 4.72 (s, 2H), 4.66-4.62 (m, 1H), 3.83 (bs, 2H), 2.74-2.61 (m, 1H), 2.37-2.24 (m, 1H), 2.02-1.87 (m, 1H), 1.80-1.61 (m, 1H), 1.48 (d, J=6.9 Hz, 3H), 1.42 (s, 9H), 1.28 (d, J=7.0 Hz, 3H); MS: 600 (M+Na).sup.+

Example 19

Synthesis of (R,E)-3-methyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5, 8(9H)-trione (1b)

(72) To a solution of compound 20a (200 mg, 0.3 mmol) in 10 mL of CH.sub.2Cl.sub.2 at 0 C. was added 2 ml of trifluroacetic acid. After stirring at 0 C. for 2 h, solvents were evaporated. The residue was dissolved in ethylacetate washed with saturated sodium bicarbonate. The organic layer was concentrated in vacuo and the residue was taken in toluene (50 mL) and 337 mg of 2-hydroxy pyridine was added and stirred at 40 C. for 40 h, concentrated the reaction mixture ethyl acetate 50 mL was added and washed with saturated sodium bicarbonate solution (20 mL), organic phase was concentrated and purified by column chromatography using CH.sub.2Cl.sub.2/MeOH (19:1) to yield compound 1b (33 mg, 30%) as off white solid.

(73) .sup.1H NMR (500 MHz, CD.sub.3OD): 7.48 (d, J=7.3 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.23-7.16 (m, 2H), 6.50 (d, J=15.6 Hz, 1H), 6.08-6.02 (m, 1H), 4.40 (q, J=7.3 Hz, 1H), 3.92-3.82 (m, 2H), 2.38-2.35 (m, 2H), 2.31-2.29 (m, 1H), 2.24-2.18 (m, 1H), 1.99-1.95 (m, 1H), 1.78-1.73 (m, 1H), 1.50 (d, J=7.3 Hz, 3H); .sup.13C NMR (125 MHz, CD.sub.3OD): 176.9, 174.6, 173.4, 135.7, 135.2, 134.0, 129.7, 129.3, 128.6, 128.4, 128.2, 52.7, 45.5, 35.9, 33.1, 24.7, 17.9; MS: 338 (M+Na).sup.+;

Example 20

Synthesis of (3R,9S,E)-3,9-dimethyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1d)

(74) To a solution of compound 20b (180 mg, 0.3 mmol) in 10 mL of CH.sub.2Cl.sub.2 at 0 C. was added 2 ml of trifluroacetic acid. After stirring at 0 C. for 2 h, solvents were evaporated. The residue was dissolved in ethylacetate washed with saturated sodium bicarbonate. The organic layer was concentrated in vacuo and the residue was taken in toluene (50 mL) and 296 mg of 2-hydroxy pyridine was added and stirred at 40 C. for 40 h, concentrated the reaction mixture ethyl acetate 50 mL was added and washed with saturated sodium bicarbonate solution (20 mL), organic phase was concentrated and purified by column chromatography using CH.sub.2Cl.sub.2/MeOH (19:1) to yield compound 1d (25 mg, 25%) as off white solid.

(75) .sup.1H NMR (400 MHz, CD.sub.3OD): 7.45 (t, J=6.7 Hz, 1H), 7.22-7.14 (m, 3H), 6.45 (d, J=15.3 Hz, 1H), 6.11-6.04 (m, 1H), 4.42 (q, J=7.3 Hz, 1H), 4.25 (d, J=14.5 Hz, 1H), 3.51 (d, J=14.5 Hz, 1H), 2.45-2.34 (m, 2H), 2.55-2.18 (m, 1H), 2.24-2.18 (m, 1H), 1.72-1.62 (m, 2H), 1.48 (d, J=7.3 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H); MS: 352 (M+Na).sup.+;

Example 21

Synthesis of (R)-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1c)

(76) To a solution of compound 1b (10 mg, 0.03 mmol) in 3 mL ethanol 5 mg of 10% Pd on activated charcoal was added and stirred under hydrogen for 10h, then filtered the reaction mixture and concentrated to yield compound 1c (9 mg, 90%) as off white solid.

(77) .sup.1H NMR (500 MHz, DMSO-d.sub.6): 9.06 (bs, 1H), 8.45 (d, J=6.8 Hz, 1H), 8.33-8.31 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.22-7.11 (m, 3H), 4.43-4.40 (m, 1H), 3.82-3.78 (m, 1H), 3.71-3.67 (m, 1H), 2.38-2.32 (m, 2H), 2.13-2.05 (m, 2H), 1.64-1.61 (m, 1H), 1.47-1.35 (m, 5H), 1.32 (d, J=6.6 Hz, 3H); .sup.13C NMR (125 MHz, DMSO-d.sub.6): 173.2, 171.2, 170.7, 136.7, 136.0, 130.2, 126.5, 125.9, 125.2, 49.7, 43.1, 34.8, 31.9, 31.1, 27.8, 24.8, 17.0; MS: 340 (M+Na).sup.+;

Example 22

Synthesis of (3R,9S)-3,9-dimethyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1e)

(78) To a solution of compound 1d (10 mg, 0.03 mmol) in 3 mL ethanol 5 mg of 10% Pd on activated charcoal was added and stirred under hydrogen for 10h, then filtered the reaction mixture and concentrated to yield compound 1e (8 mg, 80%) as off white solid.

(79) .sup.1H NMR (500 MHz, DMSO-d.sub.6): 9.14 (bs, 1H), 8.73 (d, J=7.0 Hz, 1H), 8.49-8.47 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.17-7.12 (m, 2H), 7.08-7.04 (m, 1H), 4.44-4.41 (m, 1H), 4.20-4.16 (m, 1H), 4.06-4.02 (m, 1H), 2.36-2.28 (m, 3H), 1.44-1.33 (m, 3H), 1.30 (d, J=7.0 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H); MS: 354 (M+Na).sup.+;

Example 23

Synthesis of (3R)-12,13-dihydroxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1h)

(80) To a stirred solution of 1b (25 mg, in tBuOH-water (3 ml, 1:1), NMO (50% aq. Solution) 74 l and OsO.sub.4 (2.5% in tBuOH) 40 l were added and stirred for 6h, concentrated the reaction mixture diluted with ethylacetate, washed with saturated sodium thio sulfate and brine, organic layer was concentrated and purified by column chromatography CH.sub.2Cl.sub.2/MeOH (9:1) afforded compound 1h as diasteromeric mixture in quantitative yield.

(81) .sup.1H NMR (500 MHz, CD.sub.3OD) (mixture of diastereomers) 7.60-7.56 (m, 2H), 7.37 (bs, 1H), 7.30-7.28 (m, 2H), 6.63 (bs, 1H), 5.39-5.35 (m, 1H), 4.66-4.63 (m, 1H), 4.46-4.42 (m, 1H), 4.00 (d, J=14.6 Hz, 1H), 3.71 (d, J=14.6 Hz, 1H), 3.61-3.58 (m, 2H), 2.36-2.32 (m, 4H), 2.10-2.06 (m, 2H), 1.70-1.62 (m, 6H), 1.53-1.50 (m, 6H); MS: 372 (M+Na).sup.+.

Example 24

(R)-tert-butyl(2-((1-((2-iodo-5-methoxyphenyl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamate (17b)

(82) To a mixture of 2-iodo 4-methoxy aniline 2c (1.0 g, 4.0 mmol), Boc-Gly-D-Ala-OH (987 mg, 4.0 mmol) in 20 mL CH.sub.2Cl.sub.2. HATU (2.3 g, 6.0 mmol), diisopropyl ethylamine (2.0 mL) were added and stirred for 14 h at 25 C., the reaction mixture was diluted with CH.sub.2Cl.sub.2 (30 mL) and washed with 1N HCl (15 mL) and sat. NaHCO.sub.3 solution (15 mL) organic layer was separated, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure. Purification by column chromatography with EtOAc/CH.sub.2Cl.sub.2 (2:3) yielded compound 17b (1.2 g, 63%) as a yellow color sticky liquid.

(83) .sup.1H NMR (200 MHz, CDCl.sub.3): 8.07 (bs, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 6.82-6.78 (m, 1H), 6.50 (dd, J=8.8, 2.8 Hz, 1H), 5.16 (bs, 1H), 4.75-4.62 (m, 1H), 3.88 (d, J=6.0 Hz, 2H), 3.79 (s, 3H), 1.49 (d, J=7.3 Hz, 3H), 1.45 (s, 9H); MS: 500 (M+Na).sup.+.

Example 25

Synthesis of (R,E)-2,2,2-trichloroethyl 6-(2-(2-(2-((tert-butoxycarbonyl)amino) acetamido) propanamido)-4-methoxyphenyl)hex-5-enoate (20c)

(84) To a solution of compound 19 (500 mg, 2 mmol) and compound 17b (1.0 g, 2.1 mmol) in anhydrous acetonitrile, Pd(OAc).sub.2 (7 mg, 1.6 mol %) and triethylamine (2.8 mL) were added and heated at 85 C. for 12h, then the reaction mixture was concentrated in vacuo. Purification by column chromatography with EtOAc/CH.sub.2Cl.sub.2 (2:3) yielded compound 20c (800 mg, 66%) as colorless liquid.

(85) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24 (bs, 1H), 7.58-7.54 (m, 1H), 7.12-7.07 (m, 1H), 6.70-6.67 (m, 1H), 6.43 (d, J=16.1 Hz, 1H), 6.00-5.93 (m, 1H), 5.44 (bs, 1H), 4.75 (s, 2H), 4.73-4.69 (m, 1H), 3.91-3.80 (m, 2H), 3.78 (s, 3H), 2.55 (t, J=7.3 Hz, 2H), 2.32 (q, J=7.3 Hz, 1H), 1.91 (quin, J=6.5, 14.7 Hz), 1.48 (d, J=7.3 Hz, 3H), 1.43 (s, 9H); MS: 616 (M+Na).sup.+;

Example 26

Synthesis of (R,E)-16-methoxy-3-methyl-3,4,6,7,10,11-hexahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1f)

(86) To a solution of compound 20c (200 mg, 0.3 mmol) in 10 mL of CH.sub.2Cl.sub.2 at 0 C. was added 2 ml of trifluroaceticacid. After stirring at 0 C. for 2 h, solvents were evaporated; the residue was dissolved in ethylacetate washed with saturated sodium bicarbonate. The organic layer was concentrated in vacuo. The residue was taken in toluene (50 mL) and 320 mg of 2-hydroxy pyridine was added and stirred at 40 C. for 40 h, concentrated the reaction mixture in vacuo ethyl acetate 50 ml was added and washed with saturated sodium bicarbonate solution (20 mL), organic phase was concentrated under reduced pressure and purified by column chromatography using CH.sub.2Cl.sub.2/MeOH (19:1) to yield compound 1f (38 mg, 33%) as white solid.

(87) .sup.1H NMR (500 MHz, CD.sub.3OD): 7.42 (d, J=9.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.80-6.78 (m, 1H), 6.45 (d, J=15.0 Hz, 1H), 5.99-5.93 (m, 1H), 4.47 (q, J=7.5 Hz, 1H), 3.95-3.85 (m, 2H), 3.80 (s, 3H), 2.38-2.35 (m, 2H), 2.28-2.25 (m, 1H), 2.02-1.96 (m, 1H), 1.82-1.73 (m, 2H), 1.51 (d, J=7.5 Hz, 3H); MS: 368 (M+Na).sup.+.

Example 27

Synthesis of (R)-16-methoxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1g)

(88) To a solution of compound 1f (20 mg, 0.03 mmol) in 3 mL ethanol 5 mg of 10% Pd on activated charcoal was added and stirred under hydrogen for 10h, then filtered the reaction mixture and concentrated to yield compound 1g (15 mg, 75%) as off white solid.

(89) .sup.1H NMR (200 MHz, CD.sub.3OD): 7.96-7.94 (m, 1H), 7.56-7.44 (m, 1H), 7.17-7.07 (m, 1H), 4.10 (q, J=7.0 Hz, 1H), 3.99-3.89 (m, 1H), 3.75 (s, 3H), 3.65-3.60 (m, 1H), 2.55-2.17 (m, 4H), 1.81-1.42 (m, 9H); MS: 370 (M+Na).sup.+.

Example 28

Synthesis of (3R)-12,13-dihydroxy-16-methoxy-3-methyl-3,4,6,7,10,11,12,13-octahydro-1H-benzo[h][1,4,7]triazacyclopentadecine-2,5,8(9H)-trione (1i)

(90) To a stirred solution of 1f (25 mg, in tBuOH-water (3 ml, 1:1), NMO (50% aq. Solution) 67 l and OsO.sub.4 (2.5% in tBuOH) 38 l were added and stirred for 6h, concentrated the reaction mixture diluted with ethylacetate, washed with saturated sodium thio sulfate and brine, organic layer was concentrated and purified by column chromatography CH.sub.2Cl.sub.2/MeOH (9:1) afforded compound 1i as diasteromeric mixture in quantitative yield.

(91) .sup.1H NMR (400 MHz, CD.sub.3OD) (mixture of diastereomers) 7.55 (bs, 1H), 7.19 (d, J=7.0 Hz, 1H), 6.81 (d, J=7.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.60 (bs, 1H), 4.83-4.75 (m, 1H), 4.60-4.42 (m, 3H), 4.10-3.89 (m, 2H), 3.77 (bs, 6H), 3.71-3.63 (m, 4H), 2.41-2.15 (m, 4H), 2.12-2.01 (m, 2H), 1.80-1.54 (m, 6H), 1.47-1.40 (m, 6H); MS: 402 (M+Na).sup.+.

Example 29

tert-Butyl((3R,4S,5R)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxy-5-methylhept-6-en-3-yl)carbamate (25a) and tert-butyl((3R,4R,5R)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxy-5-methylhept-6-en-3-yl)carbamate (25b)

(92) Anhydrous chromium (II) chloride (4.6 g, 37.5 mmol) was transferred into a round bottomed flask under argon atmosphere and heated upto 200 C. for 40 min under high vaccum. (R)-tert-butyl(4-((tert-butyldimethylsilyl)oxy)-1-oxobutan-2-yl)carbamate 24 (4.0 g, 12.6 mmol) in THF (40 mL) was added at 0 C. followed by trans-crotyl bromide (2.6 mL, 25 mmol) and the reaction mixture was stirred at 23 C. for 8 h. Reaction mass was quenched with saturated aq. NH.sub.4Cl (20 mL) and extracted with Et.sub.2O (4100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200 mesh, 1:15 to 1:10 ethyl acetate-pet ether) to afford 25b and 25a respectively (2:1 ratio, 75%).

(93) 25a: (1.2 g, 26%) as a colourless oil. [].sub.D.sup.27=5.7 (c=0.9, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3441, 2958, 2885, 1701, 1500; .sup.1H NMR (400 MHz, CDCl.sub.3): 5.83 (m, 1H), 5.09-5.05 (m, 3H), 3.85 (bs, 1H), 3.70-3.69 (m, 2H), 3.36 (bs, 1H), 2.86-2.85 (m, 1H), 2.30-2.24 (m, 1H), 1.82-1.66 (m, 2H), 1.41 (s, 9H), 1.01 (d, J=6.4 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 155.7, 141.0, 115.8, 79.1, 76.6, 59.8, 50.3, 41.2, 31.1, 28.4 (3C), 25.9 (3C), 18.2, 16.9, 5.5 (2C); MS: 396 (M+Na).sup.+;

(94) 25b: (2.3 g, 49%) as a colourless oil. [].sub.D.sup.27=7.6 (c=0.4, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3443, 2957, 2859, 1716, 1473; .sup.1H NMR (400 MHz, CDCl.sub.3): 5.83-5.78 (m, 1H), 5.10-5.08 (m, 3H), 3.84-3.83 (m, 1H), 3.70-3.67 (m, 2H), 3.32 (bs, 1H), 3.06 (bs, 1H), 2.24-2.22 (m, 1H), 1.81-1.70 (m, 2H), 1.41 (s, 9H), 1.03 (d, J=7.4 Hz, 3H), 0.88 (s, 9H), 0.04 (d, J=1.6 Hz, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 156.2, 141.0, 115.7, 79.0, 76.3, 60.0, 49.6, 41.6, 35.8, 28.4 (3C), 25.9 (3C), 18.2, 16.9, 5.5 (2C); MS: 396 (M+Na).sup.+;

Example 30

(4R,5R)-5-((R)-But-3-en-2-yl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)oxazolidin-2-one (26 b)

(95) To a stirred solution of 25b (0.3 g, 0.8 mmol) in dry THF (10 mL), NaH (60% in mineral oil, 0.070 g, 1.7 mmol) was added at 0 C. then reaction mass was heated at 60 C. for 2 h. The Reaction mass was cooled to 0 C. and quenched with saturated aq. NH.sub.4Cl solution (5 mL), extracted with ethyl acetate (220 mL), dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200 mesh, 3:7 ethyl acetate-pet ether) to afford 26b as a white crystalline solid (0.22 g, 91%).

(96) Mp=60-61 C.; [ ].sub.D.sup.26=43.0 (c=0.5, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3242, 2929, 1756, 1256, 1100; .sup.1H NMR (400 MHz, CDCl.sub.3): 6.25 (bs, 1H), 5.78-5.69 (m, 1H), 5.12 (s, 1H), 5.08 (d, J=5.1 Hz, 1H), 4.15 (t, J=4.9 Hz, 1H), 3.70-3.64 (m, 3H), 2.40-2.45 (m, 1H), 1.73-1.64 (m, 2H), 1.09 (d, J=7.4 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 159.1, 137.0, 117.1, 85.0, 60.2, 53.4, 41.3, 38.3, 25.8 (3C), 18.1, 15.2, 5.4 (2C); MS: 322 (M+Na).sup.+;

Example 31

2-((4R,5R)-5-((R)-But-3-en-2-yl)-2-oxooxazolidin-4-yl)acetic acid (27)

(97) To a solution of 26b (1.0 g, 3.3 mmol) in THF (20 mL), TBAF (1M in THF, 5 mmol) was added and stirred for 5 h at 23 C. Reaction mass was quenched with saturated aq. NH.sub.4Cl solution (10 mL), extracted with ethyl acetate (250 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200 mesh, 1:19 MeOH-DCM) to afford (4R,5R)-5-((R)-but-3-en-2-yl)-4-(2-hydroxyethyl)oxazolidin-2-one (0.57 g, 93%) colorless oil.

(98) [ ].sub.D.sup.27=37.2 (c=1.3, CHCl.sub.3); IR .sub.max (film): cm.sup.1 3310, 2936, 1735, 1420, 1013; .sup.1H NMR (400 MHz, CDCl.sub.3): 6.93 (s, 1H), 5.75-5.66 (m, 1H), 5.12 (d, J=4.2 Hz, 1H), 5.08 (s, 1H), 4.10 (t, J=5.0 Hz, 1H), 3.72-3.61 (m, 4H), 2.45-2.40 (m, 1H), 1.70 (q, J=6.0 Hz, 2H), 1.06 (d, J=6.7 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 159.8, 136.9, 117.2, 85.5, 59.03, 53.3, 41.2, 38.0, 14.9;

(99) To a solution of (4R,5R)-5-((R)-but-3-en-2-yl)-4-(2-hydroxyethyl)oxazolidin-2-one (0.5 g, 2.7 mmol) in acetone (20 mL), Jones reagent (0.7 M solution, 15 mL) was added drop wise at 0 C. and the reaction mixture was stirred for 3.5 h at same temperature. Reaction mass was quenched with isopropanol, the solid thus formed was filtered through a celite bed and the filtrate was evaporated to dryness. The crude material was taken up in ethyl acetate (50 mL), washed with water (10 mL) and brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 27 (0.49 g, 92%) as a white solid.

(100) Mp=98-100 C.; [].sub.D.sup.25=56.0 (c=0.5, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3309, 2974, 1732, 1419, 1240; .sup.1H NMR (200 MHz, CDCl.sub.3): 8.84 (bs, 1H), 7.16 (s, 1H), 5.83-5.66 (m, 1H), 5.22 (s, 1H), 5.15 (d, J=5.5 Hz, 1H), 4.19 (t, J=4.9 Hz, 1H), 3.95 (q, J=6.4 Hz, 1H), 2.63 (d, J=6.8 Hz, 2H), 2.58-2.44 (m, 1H), 1.13 (d, J=6.9 Hz, 3H); .sup.13C NMR (50 MHz, CDCl.sub.3): 174.0, 160.3, 136.1, 118.0, 84.5, 51.4, 41.0, 39.9, 14.6; MS: 222 (M+Na).sup.+;

Example 32

2-((4R,5R)-5-((R)-But-3-en-2-yl)-2-oxooxazolidin-4-yl)-N-(3-((triisopropylsilyl)oxy)phenyl)acetamide (29)

(101) To a solution of 27 (0.2 g, 1 mmol) and HOBt (0.16 g, 1.2 mmol) in dry DCM (10 mL), DCC (0.25 g, 1.2 mmol) was added at 0 C., stirred for 10 min. Then 3-((triisopropylsilyl)oxy) aniline 28 (0.26 g, 1 mmol) was introduced and stirring continued for 16 h at room temperature. White solid thus formed was filtered through a celite bed, filtrate was evaporated and purified by column chromatography (silica gel 100-200, 1:19 MeOH-DCM) to afford 29 (0.4 g, 87%) as a white solid.

(102) Mp=110-111 C.; [ ].sub.D.sup.25=5.0 (c=0.5, CHCl.sub.3); IR .sub.max(film): cm.sup.1 2945, 2868, 1748, 1668, 1607; .sup.1H NMR (400 MHz, CDCl.sub.3): 7.96 (m, 1H), 7.23 (s, 1H), 7.14 (t, J=7.9 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.64 (m, 1H), 5.86 (m, 1H), 5.75 (m, 1H), 5.20-5.16 (m, 2H), 4.28 (m, 1H), 4.05 (m, 1H), 2.67-2.50 (m, 3H), 1.31-1.25 (m, 3H), 1.12 (d, J=7.0 Hz, 3H), 1.10 (d, J=7.6 Hz, 18H); .sup.13C NMR (100 MHz, CDCl.sub.3): 167.7, 158.4, 156.6, 138.5, 136.4, 129.6, 117.8, 116.1, 112.3, 111.6, 84.3, 51.6, 42.8, 41.3, 17.9 (3C), 14.8, 12.6 (6C); MS: 469 (M+Na).sup.+;

Example 33

(4R,5R)-4-(2-(2-Amino-4-((triisopropylsilyl)oxy)phenyl)-2-oxoethyl)-5-((R)-but-3-en-2-yl)oxazolidin-2-one (30)

(103) Compound 29 (100 mg, 0.2 mmol) was dissolved in dry acetonitrile (150 mL) and purged with argon for 15 min. This solution was irradiated with low pressure Hg vapour lamp (254 nm, 16 W) for 4.5 h. The residue obtained after the removal of the solvent under reduced pressure was purified by column chromatography (silica gel 230-400, 0.4:99.6 MeOH-DCM) to afford 30 (36 mg, 42% brsm) as a white solid.

(104) Mp=131-132 C.; [ ].sub.D.sup.26=33.8 (c=0.2, CHCl.sub.3); IR .sub.max(film): cm.sup.1 3437, 3327, 2945, 2869, 1744, 1636, 1619, 1589; .sup.1H NMR (400 MHz, CDCl.sub.3): 7.49 (d, J=8.8 Hz, 1H), 6.30 (bs, 2H), 6.19 (dd, J=8.8 Hz, 2.1 Hz, 1H), 6.10 (d, J=2.1 Hz, 1H), 5.80 (m, 1H), 5.62 (bs, 1H), 5.20-5.16 (m, 2H), 4.23 (t, J=5.2 Hz, 1H), 4.06 (m, 1H), 3.15 (m, 2H), 2.57 (m, 1H), 1.29-1.23 (m, 3H), 1.16 (d, J=6.7 Hz, 3H), 1.10 (d, J=7.3 Hz, 18H); .sup.13C NMR (100 MHz, CDCl.sub.3): 197.2, 162.0, 158.2, 153.0, 136.7, 132.8, 117.6, 112.3, 109.8, 106.3, 84.2, 51.1, 44.6, 41.2, 17.8 (3C), 14.9, 12.7 (6C); MS: 469 (M+Na).sup.+;

Example 34

(S)-2-((4R,5R)-4-(2-(2-Amino-4-((triisopropylsilyl)oxy)phenyl)-2-oxoethyl)-2-oxooxazolidin-5-yl)propanoic acid (31)

(105) To a cooled (0 C.) solution of 30 (50 mg, 0.1 mmol) in dioxane-water (3:1, 4 mL) OsO.sub.4 (2.5% in t-BuOH, 0.1 mL, 0.01 mmol), NaIO.sub.4(96 mg, 0.4 mmol) and 2,6-lutidine (0.03 mL, 0.2 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, filtered, and concentrated under vacuum. The residue obtained was taken up in ethyl acetate (10 mL), washed with aq.Na.sub.2S.sub.2O.sub.3 (5 mL) followed by brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford colorless oil.

(106) To this crude material dissolved in t-BuOH-water (5:1, 3 mL), NaH.sub.2PO.sub.4 (20 mg, 0.16 mmol), 2-methyl-2-butene (0.03 mL, 0.3 mmol) and NaClO.sub.2 (10 mg, 0.1 mmol) were added. After the reaction mixture was stirred at 23 C. for 6 h, the reaction mixture was evaporated to dryness, dissolved in ethyl acetate (10 mL), washed with water (5 mL), and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200 mesh, 1:12, MeOH-DCM) to afford 31 (32 mg, 61%) as an off white solid.

(107) Mp=105-106 C.; [].sub.D.sup.25=80.5 (c=0.5, CHCl.sub.3); IR .sub.max (film): cm.sup.1: 3338, 2925, 2854, 1738, 1614, 1519, 1015; .sup.1H NMR (400 MHz, CD.sub.3OD): 7.63 (d, J=8.8 Hz, 1H), 6.23 (d, J=2.2 Hz, 1H), 6.15 (dd, J=2.2, 8.8 Hz, 1H), 4.64-4.59 (m, 1H), 4.23-4.20 (m, 1H), 3.29-3.25 (m, 2H), 2.89-2.83 (m, 1H), 1.29-1.27 (m, 3H), 1.22 (d, J=7.0 Hz, 3H), 1.15-1.11 (m, 18H); .sup.13C NMR (100 MHz, CD.sub.3OD): 198.8, 162.9, 161.2, 134.4, 113.6, 110.0, 107.0, 83.8, 53.0, 46.0, 45.5, 18.4 (6C), 13.9 (3C), 12.4. MS: 487 (M+Na).sup.+;

(108) The present invention provides a novel synthetic route for bulk production of naturally occurring valuable compounds. Further the preparation of the solomonamide class of biologically active molecules by means of novel chemical synthesis provides sufficient yield and purity of the desired compounds that emphasizes the economic significance and technical advancement of the instant invention.